Compounds for treating proliferative diseases

ABSTRACT

The present disclosure provides compounds of Formula (I). The compounds described herein may be useful in treating and/or preventing proliferative diseases (e.g., cancer). Also provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including or using a compound described herein.

RELATED APPLICATIONS

This application is a division of U.S. patent application, U.S. Ser. No.15/779,685, filed May 29, 2018, which is a national stage filing under35 U.S.C. § 371 of international PCT application, PCT/US2016/064256,filed Nov. 30, 2016, which claims priority under 35 U.S.C. § 119(e) toU.S. Provisional Application, U.S. Ser. No. 62/261,240, filed Nov. 30,2015, each of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

The spread of cancer cells from a primary tumor site to distant organsis known as metastasis. The progression of human cancer to metastaticdisease is the major contributing factor to its lethality. Metastasishas been considered one of the most intriguing aspects of thepathogenesis of cancer, where cancer is a type of proliferative disease.Cancer tumor metastasis, or otherwise known as metastatic disease, isresponsible for most therapeutic failures in treating the disease, aspatients succumb to the multiple tumor growth, accounting for more than90% of human cancer-related deaths. See, for example, Cancer, AComprehensive Treatise, F. F. Becker (Editor), Volume 4, Chapter 3,Plenum Press, New York, 1975.

Thus, there is a need for novel therapies to inhibit growth and increasethe death of metastatic tumor cells.

SUMMARY OF THE INVENTION

The present disclosure provides compounds, such as compounds of Formula(I). The compounds described herein may be useful in treating and/orpreventing proliferative diseases (e.g., cancer (e.g., lung cancer,breast cancer, leukemia, lymphoma, melanoma, multiple myeloma, Ewing'ssarcoma, osteosarcoma, brain cancer, neuroblastoma), benign neoplasms,angiogenesis, inflammatory diseases, autoinflammatory diseases, andautoimmune diseases). Also provided are pharmaceutical compositions,kits, methods, and uses of a compound described herein.

In one aspect, the present disclosure provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R¹, R², R³, and R⁴ are described herein.

Exemplary compounds of Formula (I) include, but are not limited to:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof.

In another aspect, the present disclosure provides pharmaceuticalcompositions including a compound described herein, and optionally apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutical compositions described herein include an effective amountof a compound described herein. An effective amount described herein maybe a therapeutically effective amount or prophylactically effectiveamount. The pharmaceutical composition may be useful for treating aproliferative disease in a subject in need thereof and/or preventing aproliferative disease in a subject in need thereof.

In certain embodiments, a proliferative disease being treated and/orprevented is cancer. In certain embodiments, the cancer is metastaticcancer.

In certain embodiments, the subject being treated is a mammal (e.g.,human or non-human mammal).

Another aspect of the present disclosure relates to methods of treatingand/or preventing a proliferative disease in a subject.

In certain embodiments, the method described herein includesadministering to the subject an effective amount of a compound, orpharmaceutical composition thereof, described herein.

Another aspect of the present disclosure relates to a method ofcontacting a cell with an effective amount of a compound, orpharmaceutical composition thereof, as described herein. In certainembodiments, a ceil contacted with an effective amount of a compound orpharmaceutical composition described herein is in vitro or in vivo. Incertain embodiments, the method further includes administering to thesubject an additional pharmaceutical agent.

Another aspect of the present disclosure relates to a method ofcontacting the cell with an additional pharmaceutical agent. In certainembodiments, the method further includes performing radiotherapy,immunotherapy, and/or transplantation on the subject.

Another aspect of the present disclosure relates to kits comprising acontainer with a compound, or pharmaceutical composition thereof, asdescribed herein. The kits described herein may include a single dose ormultiple doses of the compound or pharmaceutical composition. The kitsmay be useful in a method of the disclosure. In certain embodiments, thekit further includes instructions for using the compound orpharmaceutical composition.

In yet another aspect, the present disclosure provides compounds andpharmaceutical compositions described herein for use in a method of thedisclosure.

The details of one or more embodiments of the disclosure are set forthherein. Other features, objects, and advantages of the disclosure willbe apparent from the Detailed Description, the Examples, and the Claims.

Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics. 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987. The disclosure is not intended to belimited in any manner by the exemplary listing of substituents describedherein.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The disclosure additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆.

The term “aliphatic” includes both saturated and unsaturated, straightchain (i.e., unbranched), branched, acyclic, cyclic, or polycyclicaliphatic hydrocarbons, which are optionally substituted with one ormore functional groups. As will be appreciated by one of ordinary skillin the art, “aliphatic” is intended herein to include, but is notlimited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, andcycloalkynyl moieties. Thus, the term “alkyl” includes straight,branched and cyclic alkyl groups. An analogous convention applies toother generic terms such as “alkenyl”, “alkynyl”, and the like.Furthermore, the terms “alkyl”, “alkenyl”, “alkynyl”, and the likeencompass both substituted and unsubstituted groups. In certainembodiments, “lower alkyl” is used to indicate those alkyl groups(cyclic, acyclic, substituted, unsubstituted, branched or unbranched)having 1-6 carbon atoms.

In certain embodiments, the alkyl, alkenyl, and alkynyl groups employedin the disclosure contain 1-20 aliphatic carbon atoms. In certain otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-10 aliphatic carbon atoms. In yet otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-8 aliphatic carbon atoms. In still otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-6 aliphatic carbon atoms. In yet other embodiments,the alkyl, alkenyl, and alkynyl groups employed in the disclosurecontain 1-4 carbon atoms. Illustrative aliphatic groups thus include,but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl,cyclopropyl, —CH₂-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl,isobutyl, tert-butyl, cyclobutyl, —CH₂-cyclobutyl, n-pentyl, sec-pentyl,isopentyl, tert-pentyl, cyclopentyl, —CH₂-cyclopentyl, n-hexyl,sec-hexyl, cyclohexyl, —CH₂-cyclohexyl moieties and the like, whichagain, may bear one or more substituents. Alkenyl groups include, butare not limited to, for example, ethenyl, propenyl, butenyl,l-methyl-2-buten-1-yl, and the like. Representative alkynyl groupsinclude, but are not limited to, ethynyl, 2-propynyl (propargyl),1-propynyl, and the like.

The term “alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), propyl(C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl,sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl,neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g.,n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈), and the like. Unless otherwise specified, each instance ofan alkyl group is independently unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents(e.g., halogen, such as F). In certain embodiments, the alkyl group isan unsubstituted C₁₋₁₀, alkyl (such as unsubstituted C₁₋₆ alkyl, e.g.,—CH₃). In certain embodiments, the alkyl group is a substituted C₁₋₁₀alkyl (such as substituted C₁₋₆ alkyl, e.g., —CF₃).

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadicnyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl. Incertain embodiments, the alkenyl group is substituted C₁₋₁₀ alkenyl. Inan alkenyl group, a double bond for which the stereochemistry is notspecified (e.g., —CH═CHCH₃ or

may be an (E)- or (Z)-double bond.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In someembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms(“C₂₋₅ alkynyl”). In some embodiments, an alkynyl group has 2 to 4carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, an alkynyl group has2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynylgroup has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbontriple bonds can be internal (such as in 2-butynyl) or terminal (such asin 1-butynyl). Examples of C₂₋₄ alkynyl groups include, withoutlimitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅),hexynyl (C₆), and the like. Additional examples of alkynyl includeheptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified,each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclic ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclic ring, and m such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₁₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₁₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system,such as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclic ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclicring, or ring systems wherein the heterocyclic ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclic ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclic ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents, hi certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl, Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-numbered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatominclude, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pielectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Unlessotherwise specified, each instance of an aryl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is unsubstituted C₆₋₁₄ aryl. Incertain embodiments, the aryl group is substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of alkyl and aryl and refers to an optionallysubstituted alkyl group substituted by an optionally substituted arylgroup. In certain embodiments, the aralkyl is optionally substitutedbenzyl. In certain embodiments, the aralkyl is benzyl. In certainembodiments, the aralkyl is optionally substituted phenethyl. In certainembodiments, the aralkyl is phenethyl.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl, and thiophenyl.Exemplary 5-membered heteroaryl groups containing two heteroatomsinclude, without limitation, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroarylgroups containing three heteroatoms include, without limitation,triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-memberedheteroaryl groups containing four heteroatoms include, withoutlimitation, tetrazolyl. Exemplary 6-membered heteroaryl groupscontaining one heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryl groups containing two heteroatomsinclude, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or fourheteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing oneheteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl and refers to anoptionally substituted alkyl group substituted by an optionallysubstituted heteroaryl group.

“Unsaturated” or “partially unsaturated” refers to a group that includesat least one double or triple bond. A “partially unsaturated” ringsystem is further intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aromatic groups (e.g., arylor heteroaryl groups). Likewise, “saturated” refers to a group that doesnot contain a double or triple bond, i.e., contains all single bonds.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocycyl, aryl, and heteroarylgroups, which are divalent bridging groups, are further referred tousing the suffix -ene, e.g., alkylene, alkenylene, alkynylene,carbocyclylene, heterocyclylene, arylene, and heteroarylene.

An atom, moiety, or group described herein may be unsubstituted orsubstituted, as valency permits, unless otherwise provided expressly.The term “optionally substituted” refers to substituted orunsubstituted.

A group is optionally substituted unless expressly provided otherwise.The term “optionally substituted” refers to being substituted orunsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl,carbocyclyl, heterocycyl, aryl, and heteroaryl groups are optionallysubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted”or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl,“substituted” or “unsubstituted” carbocyclyl, “substituted” or“unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or“substituted” or “unsubstituted” heteroaryl group). In general, the term“substituted”, whether preceded by the term “optionally” or not, meansthat at least one hydrogen present on a group (e.g., a carbon ornitrogen atom) is replaced with a permissible substituent, e.g., asubstituent which upon substitution results in a stable compound, e.g.,a compound which does not spontaneously undergo transformation such asby rearrangement, cyclization, elimination, or other reaction. Unlessotherwise indicated, a “substituted” group has a substituent at one ormore substitutable positions of the group, and when more than oneposition in any given structure is substituted, the substituent iseither the same or different at each position. The term “substituted” iscontemplated to include substitution with all permissible substituentsof organic compounds, any of the substituents described herein thatresults in the formation of a stable compound. The present disclosurecontemplates any and all such combinations in order to arrive at astable compound. For purposes of this disclosure, heteroatoms such asnitrogen may have hydrogen substituents and/or any suitable substituentas described herein which satisfy the valencies of the heteroatoms andresults in the formation of a stable moiety. In certain embodiments, thesubstituent is a carbon atom substituent. In certain embodiments, thesubstituent is a nitrogen atom substituent. In certain embodiments, thesubstituent is an oxygen atom substituent. In certain embodiments, thesubstituent is a sulfur atom substituent.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),SSR^(cc), —C(O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(O)NR^(bb)SO₂R^(aa), —NR^(bb)SO₂R^(aa),—SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa), —S(═O)R^(aa),—OS(O)R^(aa), —Si(R^(aa))₃, —OSi(R^(aa))₃—C(═S)N(R^(bb))₂,—C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa), —SC(═O)SR^(aa),—OC(═O)SR^(aa), —SC(═O)R^(aa), —SC(═O)R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂,—P(═O)(N(R^(bb))₂)₂, —OP(═O)(N(R^(bb))₂)₂, —NR^(bb)P(═O)(R^(aa))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(N(R^(bb))₂)₂, —P(R^(cc))₂,—P(OR^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₃ ⁺X⁻, —P(R^(cc))₄,—P(OR^(cc))₄, —OP(R^(cc))₂, —OP(R^(cc))₃ ⁺X⁻, —OP(OR^(cc))₂,—OP(OR^(cc))₃ ⁺X⁻, —OP(R^(cc))₄, —OP(OR^(cc)), —B(R^(aa))₂,—B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;wherein X— is a counterion;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)(N(R^(cc))₂)₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;wherein X is a counterion;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(bb))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), SO₂OR^(ee), OSO₂R^(ee),S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₂, —C(═S)N(R^(ff))₂,—C(O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)(OR^(ee)),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S; wherein X is a counterion;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, OC₁₋₆ alkyl, —ON (C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(O)N(C₁₋₆ alkyl)₂,NHC(═O)NH(C₁₋₆ alkyl), —NHC(O)NH₂, —C(═NH)(C₁₋₆ alkyl), OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

In certain embodiments, exemplary carbon atom substituents include, butare not limited to, halogen, —OH, —CO₂H, —CHO, —CO₂R^(aa),—C(═O)N(R^(bb))₂, —ON(R^(bb)), acyl, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted:

or two geminal hydrogens on a carbon atom are replaced with the group═O, or ═S;

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted; and

each instance of R^(bb) is, independently selected from hydrogen, —OH,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. An anionic counterion may be monovalent (i.e.,including one formal negative charge). An anionic counterion may also bemultivalent (i.e., including more than one formal negative charge), suchas divalent or trivalent. Exemplary counterions include halide ions(e.g., F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HCO₃ ⁻, HSO₄ ⁻,sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions(e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, gluconate, and the like), BF₄ ⁻, PF₄ ⁻, PF₆ ⁻, AsF₆ ⁻, SbF₆⁻, B[3,5-(CF₃)₂C₆H₃]₄]⁻, B(C*₆F₅)₄ ⁻, BPh₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, andcarborane anions (e.g., CB₁₁H₁₂ ⁻ or (HCB₁₁Me₅Br₆)⁻). Exemplarycounterions which may be multivalent include CO₃ ²⁻, HPO₄ ²⁻, PO₄ ³⁻,B₄O₇ ²⁻, SO₄ ²⁻, S₂O₃ ²⁻, carboxylate anions (e.g., tartrate, citrate,fumarate, maleate, malate, malonate, gluconate, succinate, glutarate,adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates,aspartate, glutamate, and the like), and carboranes.

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), OT iodine (iodo, —I).

“Acyl” refers to a moiety selected from the group consisting of—C(═O)R^(aa), —CHO, —CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(—NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), or —C(═S)SR^(aa), wherein R^(aa) andR^(bb) are as defined herein.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)(OR^(cc))₂, —P(═O)(R^(aa))₂, —P(═O)(N(R^(cc))₂)₂, C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ carbocyclyl,3-14 membered heterocyclyl, aryl, and 5-14 membered heteroaryl, or twoR^(cc) groups attached to a nitrogen atom are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc), and R^(dd) are as defined above.

In certain embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀carbocyclyl, 3-14 membered heterocyclyl, CV H aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aralkyl, aryl, and heteroaryl is independently substitutedwith 0.1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb),R^(cc) and R^(dd) are as defined herein. Nitrogen protecting groups arewell known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acelylmethioninederivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate,ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc),vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate(Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pme), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, M-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl 1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF), N-2,7-dichloro9-fluorenylmethyleneamine, N-ferrocenylmethylanino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylidencamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenanide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

Exemplary oxygen atom substituents include, but are not limited to,—R^(aa), —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(—NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻,—P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻, —P(═O)(R^(cc))₂, —P(═O)(OR^(cc))₂, and—P(═O)(N(R^(bb))₂)₂, wherein X⁻, R^(aa), R^(bb), and R^(cc) are asdefined herein. In certain embodiments, the oxygen atom substituentpresent on an oxygen atom is an oxygen protecting group (also referredto as a hydroxyl protecting group). Oxygen protecting groups are wellknown in the art and include those described in detail in ProtectingGroups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^(rd)edition, John Wiley & Sons, 1999, incorporated herein by reference.Exemplary oxygen protecting groups include, but are not limited to,methyl, i-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM),methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4′-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″tris(levulinoyloxyphenyl)methyl, 4,4′,4″ tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutylcarbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkylp-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzylcarbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzylcarbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

Exemplary sulfur atom substituents include, but are not limited to,—R^(aa), —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. In certain embodiments, the sulfur atom substituent present on asulfur atom is a sulfur protecting group (also referred to as a thiolprotecting group). Sulfur protecting groups are well known in the artand include those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, incorporated herein by reference.

A “hydrocarbon chain” refers to a substituted or unsubstituted divalentalkyl, alkenyl, or alkynyl group. A hydrocarbon chain includes (1) oneor more chains of carbon atoms immediately between the two radicals ofthe hydrocarbon chain; (2) optionally one or more hydrogen atoms on thechain(s) of carbon atoms; and (3) optionally one or more substituents(“non-chain substituents,” which are not hydrogen) on the chain(s) ofcarbon atoms. A chain of carbon atoms consists of consecutivelyconnected carbon atoms (“chain atoms” or “carbon units”) and does notinclude hydrogen atoms or heteroatoms. However, a non-chain substituentof a hydrocarbon chain may include any atoms, including hydrogen atoms,carbon atoms, and heteroatoms. For example, hydrocarbon chain—C^(A)H(C^(B)H₂C^(C)H₃)— includes one chain atom C^(A), one hydrogenatom on C^(A), and non-chain substituent —(C^(B)H₂C^(C)H₃). The term“C_(x) hydrocarbon chain,” wherein x is a positive integer, refers to ahydrocarbon chain that includes x number of chain atom(s) between thetwo radicals of the hydrocarbon chain. If there is more than onepossible value of x, the smallest possible value of x is used for thedefinition of the hydrocarbon chain. For example, —CH(C₂H₅)— is a C₁hydrocarbon chain, and

is a C₃ hydrocarbon chain. When a range of values is used, the meaningof the range is as described herein. For example, a C₃₋₁₀ hydrocarbonchain refers to a hydrocarbon chain where the number of chain atoms ofthe shortest chain of carbon atoms immediately between the two radicalsof the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10. A hydrocarbonchain may be saturated (e.g., —(CH₂)₄—). A hydrocarbon chain may also beunsaturated and include one or more C═C and/or C═C bonds anywhere in thehydrocarbon chain. For instance, —CH═CH—(CH₂)—, —CH₂—C═C—CH— and—C═C—CH═CH— are all examples of a unsubstituted and unsaturatedhydrocarbon chain. In certain embodiments, the hydrocarbon chain isunsubstituted (e.g., —C≡C— or —(CH₂)₄—). In certain embodiments, thehydrocarbon chain is substituted (e.g., —CH(C₂H₅)— and —CF₂—). Any twosubstituents on the hydrocarbon chain may be joined to form anoptionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl ring.For instance,

are all examples of a hydrocarbon chain. In contrast, in certainembodiments,

are not within the scope of the hydrocarbon chains described herein.When a chain atom of a C_(x) hydrocarbon chain is replaced with aheteroatom, the resulting group is referred to as a C_(x) hydrocarbonchain wherein a chain atom is replaced with a heteroatom, as opposed toa C_(x-1) hydrocarbon chain. For example,

is a C₃ hydrocarbon chain wherein one chain atom is replaced with anoxygen atom.

The term “leaving group” is given its ordinary meaning in the art ofsynthetic organic chemistry and refers to an atom or a group capable ofbeing displaced by a nucleophile. Examples of suitable leaving groupsinclude, but are not limited to, halogen (such as F, Cl, Br, or I(iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy,arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy,aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates.Exemplary leaving groups include, but are not limited to, activatedsubstituted hydroxyl groups (e.g., —OC(═O)SR^(aa), —OC(═O)R^(aa),—OCO₂R^(aa), —OC(═O)N(R^(bb)), —OC(—NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —OC(—NR^(bb))N(R^(bb))₂, OS(═O)R^(aa),—OSO₂R^(aa), —OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa),—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and—OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein). In some cases, the leaving group is a sulfonic acid ester, suchas toluenesulfonate (tosylate, —OTs), methanesulfonate (mesylate, —OMs),p-bromobenzenesulfonyloxy (brosylate, —OBs), —OS(═O)₂(CF₂)₃CF₃(nonaflate, —ONf), or trifluoromethanesulfonate (triflate, —OTf). Insome cases, the leaving group is a brosylate, such asp-bromobenzenesulfonyloxy. In some cases, the leaving group is anosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, theleaving group is a sulfonate-containing group. In some embodiments, theleaving group is a tosylate group. The leaving group may also be aphosphineoxide (e.g., formed during a Mitsunobu reaction) or an internalleaving group such as an epoxide or cyclic sulfate. Other non-limitingexamples of leaving groups are water, ammonia, alcohols, ether moieties,thioether moieties, zinc halides, magnesium moieties, diazonium salts,and copper moieties.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in, J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds describedherein include those derived from suitable inorganic and organic acidsand bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound that are associatedwith a solvent, usually by a solvolysis reaction. This physicalassociation may include hydrogen bonding. Conventional solvents includewater, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and thelike. The compounds described herein may be prepared. e.g., incrystalline form, and may be solvated. Suitable solvates includepharmaceutically acceptable solvates and further include bothstoichiometric solvates and non-stoichiometric solvates. In certaininstances, the solvate will be capable of isolation, for example, whenone or more solvent molecules are incorporated in the crystal lattice ofa crystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Representative solvates include hydrates,ethanolates, and methanolates.

The term “hydrate” refers to a compound that is associated with water.Typically, the number of the water molecules contained in a hydrate of acompound is in a definite ratio to the number of the compound moleculesin the hydrate. Therefore, a hydrate of a compound may be represented,for example, by the general formula R.xH₂O, wherein R is the compound,and x is a number greater than 0. A given compound may form more thanone type of hydrate, including, e.g., monohydrates (x is 1), lowerhydrates (x is a number greater than 0 and smaller than 1, e.g.,hemihydrates (R.0.5H₂O)), and polyhydrates (x is a number greater than1, e.g., dihydrates (R.2H₂O) and hexahydrates (R.6H₂O)).

The term “tautomers” or “tautomeric” refers to two or moreinterconvertible compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or ice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim,enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The term “polymorphs” refers to a crystalline form of a compound (or asalt, hydrate, or solvate thereof) in a particular crystal packingarrangement. All polymorphs have the same elemental composition.Different crystalline forms usually have different X-ray diffractionpatterns, infrared spectra, melting points, density, hardness, crystalshape, optical and electrical properties, stability, and solubility.Recrystallization solvent, rate of crystallization, storage temperature,and other factors may cause one crystal form to dominate. Variouspolymorphs of a compound can be prepared by crystallization underdifferent conditions.

The term “prodrugs” refers to compounds that have cleavable groups andbecome by solvolysis or under physiological conditions the compoundsdescribed herein, which are pharmaceutically active in vivo. Suchexamples include, but are not limited to, choline ester derivatives andthe like, N-alkylmorpholine esters and the like. Other derivatives ofthe compounds described herein have activity in both their acid and acidderivative forms, but in the acid sensitive form often offer advantagesof solubility, tissue compatibility, or delayed release in the mammalianorganism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24,Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well knownto practitioners of the art, such as, for example, esters prepared byreaction of the parent acid with a suitable alcohol, or amides preparedby reaction of the parent acid compound with a substituted orunsubstituted amine, or acid anhydrides, or mixed anhydrides. Simplealiphatic or aromatic esters, amides, and anhydrides derived from acidicgroups pendant on the compounds described herein are particularprodrugs. In some cases it is desirable to prepare double ester typeprodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkyl esters ofthe compounds described herein may be preferred.

The term “inhibition”, “inhibiting”, “inhibit,” or “inhibitor” refer tothe ability of a compound to reduce, slow, halt or prevent activity of aparticular biological process (e.g., activity of a bromodomain and/or abromodomain-containing protein) in a cell relative to vehicle.

When a compound, pharmaceutical composition, method, use, or kit isreferred to as “selectively,” “specifically,” or “competitively” bindinga first protein or a first chromatin, the compound, pharmaceuticalcomposition, method, use, or kit binds the first protein or the firstchromatin with a higher binding affinity (e.g., not less than about2-fold, not less than about 5-fold, not less than about 10-fold, notless than about 30-fold, not less than about 100-fold, not less thanabout 1,000-fold, or not less than about 10,000-fold) than binding asecond protein or second chromatin that is different from the firstprotein and the first chromatin. When a compound, pharmaceuticalcomposition, method, use, or kit is referred to as “selectively,”“specifically,” or “competitively” modulating (e.g., increasing orinhibiting) the activity of a bromodomain-containing protein, thecompound, pharmaceutical composition, method, use, or kit modulates theactivity of the bromodomain-containing protein to a greater extent(e.g., not less than about 2-fold, not less than about 5-fold, not lessthan about 10-fold, not less than about 30-fold, not less than about100-fold, not less than about 1.000-fold, or not less than about10,000-fold) than the activity of at least one protein that is differentfrom the bromodomain-containing protein.

The term “aberrant activity” refers to activity deviating from normalactivity. The term “increased activity” refers to activity higher thannormal activity.

The terms “composition” and “formulation” are used interchangeably.

A “subject” to which administration is contemplated refers to a human(i.e., male or female of any age group, e.g., pediatric subject (e.g.,infant, child, or adolescent) or adult subject (e.g., young adult,middle-aged adult, or senior adult)) or non-human animal. In certainembodiments, the non-human animal is a mammal (e.g., primate (e.g.,cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g.,cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g.,commercially relevant bird, such as chicken, duck, goose, or turkey)).In certain embodiments, the non-human animal is a fish, reptile, oramphibian. The non-human animal may be a male or female at any stage ofdevelopment. The non-human animal may be a transgenic animal orgenetically engineered animal. A “patient” refers to a human subject inneed of treatment of a disease. The subject may also be a plant. Incertain embodiments, the plant is a land plant. In certain embodiments,the plant is a non-vascular land plant. In certain embodiments, theplant is a vascular land plant. In certain embodiments, the plant is aseed plant. In certain embodiments, the plant is a cultivated plant. Incertain embodiments, the plant is a dicot. In certain embodiments, theplant is a monocot. In certain embodiments, the plant is a floweringplant. In some embodiments, the plant is a cereal plant, e.g., maize,corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, theplant is a legume, e.g., a bean plant, e.g., soybean plant. In someembodiments, the plant is a tree or shrub.

The term “biological sample” refers to any sample including tissuesamples (such as tissue sections and needle biopsies of a tissue); cellsamples (e.g., cytological smears (such as Pap or blood smears) orsamples of cells obtained by microdissection); samples of wholeorganisms (such as samples of yeasts or bacteria); or cell fractions,fragments or organelles (such as obtained by lysing cells and separatingthe components thereof by centrifugation or otherwise). Other examplesof biological samples include blood, serum, urine, semen, fecal matter,cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus,biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy),nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccalswabs), or any material containing biomolecules that is derived from afirst biological sample. In certain embodiments, “viability” refers tocell viability.

The terms “administer,” “administering,” or “administration” refers toimplanting, absorbing, ingesting, injecting, inhaling, or otherwiseintroducing a compound described herein, or a composition thereof, in oron a subject.

The terms “treatment,” “treat,” and “treating” refer to reversing,alleviating, delaying the onset of, or inhibiting the progress of adisease described herein. In some embodiments, treatment may beadministered after one or more signs or symptoms of the disease havedeveloped or have been observed. In other embodiments, treatment may beadministered in the absence of signs or symptoms of the disease. Forexample, treatment may be administered to a susceptible subject prior tothe onset of symptoms (e.g., in light of a history of symptoms and/or inlight of exposure to a pathogen). Treatment may also be continued aftersymptoms have resolved, for example, to delay or prevent recurrence.

The terms “condition,” “disease,” and “disorder” are usedinterchangeably.

An “effective amount” of a compound described herein refers to an amountsufficient to elicit the desired biological response, i.e., treating thecondition. As will be appreciated by those of ordinary skill in thisart, the effective amount of a compound described herein may varydepending on such factors as the desired biological endpoint, thepharmacokinetics of the compound, the condition being treated, the modeof administration, and the age and health of the subject. In certainembodiments, an effective amount is a therapeutically effective amount.In certain embodiments, an effective amount is a prophylactic treatment.In certain embodiments, an effective amount is the amount of a compounddescribed herein in a single dose. In certain embodiments, an effectiveamount is the combined amounts of a compound described herein inmultiple doses.

A “therapeutically effective amount” of a compound described herein isan amount sufficient to provide a therapeutic benefit in the treatmentof a condition or to delay or minimize one or more symptoms associatedwith the condition. A therapeutically effective amount of a compoundmeans an amount of therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms, signs,or causes of the condition, and/or enhances the therapeutic efficacy ofanother therapeutic agent.

A “prophylactically effective amount” of a compound described herein isan amount sufficient to prevent a condition, or one or more symptomsassociated with the condition or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the condition. Theterm “prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

A “proliferative disease” refers to a disease that occurs due toabnormal growth or extension by the multiplication of cells (Walker,Cambridge Dictionary of Biology; Cambridge University Press: Cambridge,UK, 1990). A proliferative disease may be associated with: 1) thepathological proliferation of normally quiescent cells; 2) thepathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes such as the matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) the pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, andautoimmune diseases.

The term “angiogenesis” refers to the physiological process throughwhich new blood vessels form from pre-existing vessels. Angiogenesis isdistinct from vasculogenesis, which is the de novo formation ofendothelial cells from mesoderm cell precursors. The first vessels in adeveloping embryo form through vasculogenesis, after which angiogenesisis responsible for most blood vessel growth during normal or abnormaldevelopment. Angiogenesis is a vital process in growth and development,as well as in wound healing and in the formation of granulation tissue.However, angiogenesis is also a fundamental step in the transition oftumors from a benign state to a malignant one, leading to the use ofangiogenesis inhibitors in the treatment of cancer. Angiogenesis may bechemically stimulated by angiogenic proteins, such as growth factors(e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g.,excessive or insufficient) angiogenesis that amounts to and/or isassociated with a disease.

The terms “neoplasm” and “tumor” are used herein interchangeably andrefer to an abnormal mass of tissue wherein the growth of the masssurpasses and is not coordinated with the growth of a normal tissue. Aneoplasm or tumor may be “benign” or “malignant,” depending on thefollowing characteristics: degree of cellular differentiation (includingmorphology and functionality), rate of growth, local invasion, andmetastasis. A “benign neoplasm” is generally well differentiated, hascharacteristically slower growth than a malignant neoplasm, and remainslocalized to the site of origin. In addition, a benign neoplasm does nothave the capacity to infiltrate, invade, or metastasize to distantsites. Exemplary benign neoplasms include, but are not limited to,lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheickeratoses, lentigos, and sebaceous hyperplasias. In some cases, certain“benign” tumors may later give rise to malignant neoplasms, which mayresult from additional genetic changes in a subpopulation of the tumor'sneoplastic cells, and these tumors are referred to as “pre-malignantneoplasms.” An exemplary pre-malignant neoplasm is a teratoma. Incontrast, a “malignant neoplasm” is generally poorly differentiated(anaplasia) and has characteristically rapid growth accompanied byprogressive infiltration, invasion, and destruction of the surroundingtissue, furthermore, a malignant neoplasm generally has the capacity tometastasize to distant sites. The term “metastasis,” “metastatic,” or“metastasize” refers to the spread or migration of cancerous cells froma primary or original tumor to another organ or tissue and is typicallyidentifiable by the presence of a “secondary tumor” or “secondary cellmass” of the tissue type of the primary or original tumor and not ofthat of the organ or tissue in which the secondary (metastatic) tumor islocated. For example, a prostate cancer that has migrated to bone issaid to be metastasized prostate cancer and includes cancerous prostatecancer cells growing in bone tissue.

The term “cancer” refers to a class of diseases characterized by thedevelopment of abnormal cells that proliferate uncontrollably and havethe ability to infiltrate and destroy normal body tissues. See, e.g.,Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins:Philadelphia, 1990. Exemplary cancers include, but are not limited to,hematological malignancies. Additional exemplary cancers include, butare not limited to, acoustic neuroma; adenocarcinoma; adrenal glandcancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma,lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benignmonoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma);bladder cancer; breast cancer (e.g., adenocarcinoma of the breast,papillary carcinoma of the breast, mammary cancer, medullary carcinomaof the breast); brain cancer (e.g., meningioma, glioblastomas, glioma(e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchuscancer; carcinoid tumor; cervical cancer (e.g., cervicaladenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma;colorectal cancer (e.g., colon cancer, rectal cancer, colorectaladenocarcinoma); connective tissue cancer; epithelial carcinoma;ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma, multipleidiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterinecancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of theesophagus, Barrett's adenocarcinoma); Ewing's sarcoma; ocular cancer(e.g., intraocular melanoma, retinoblastoma); familiarhypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomachadenocarcinoma); gastrointestinal stromal tumor (GIST); germ cellcancer; head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma), throatcancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)); heavy chain disease (e.g., alpha chaindisease, gamma chain disease, mu chain disease; hemangioblastoma;hypopharynx cancer: inflammatory myofibroblastic tumors; immunocyticamyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor,renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC),malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, smallcell lung cancer (SCLC), non-small cell lung cancer (NSCLC),adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g.,systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS);mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera(PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM)a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronicmyelocytic leukemia (CML), chronic neutrophilic leukemia (CNL),hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g.,neurofibromatosis (NF) type 1 or type 2, schwannomatosis);neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrinetumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer);ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma,ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer(e.g., pancreatic adenocarcinoma, intraductal papillary mucinousneoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget'sdisease of the penis and scrotum); pinealoma; primitive neuroectodermaltumor (PNT); plasma cell neoplasia; paraneoplastic syndromes;intraepithelial neoplasms; prostate cancer (e.g., prostateadenocarcinoma); rectal cancer; rhabdomyosarcoma: salivary gland cancer;skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA),melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g.,appendix cancer); soft tissue sarcoma (e.g., malignant fibroushistiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor(MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous glandcarcinoma; small intestine cancer; sweat gland carcinoma; synovioma;testicular cancer (e.g., seminoma, testicular embryonal carcinoma);thyroid cancer (e.g., papillary carcinoma of the thyroid, papillarythyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer;vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

The term “hematological malignancy” refers to tumors that affect blood,bone marrow, and/or lymph nodes. Exemplary hematological malignanciesinclude, but are not limited to, leukemia, such as acute lymphocyticleukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia(AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML)(e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL)(e.g., B-cell CLL, T-cell CLL)); lymphoma, such as Hodgkin lymphoma (HL)(e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g.,B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuselarge B-cell lymphoma (DLBCL, e.g., activated B-cell (ABC) DLBCL(ABC-DLBCL))), follicular lymphoma, chronic lymphocytic leukemia/smalllymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginalzone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT)lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zoneB-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma,Waldenström's macroglobulinemia (WM, lymphoplasmacytic lymphoma), hairycell leukemia (HCL), immunoblastic large cell lymphoma, precursorB-lymphoblastic lymphoma, central nervous system (CNS) lymphoma (e.g.,primary CNS lymphoma and secondary CNS lymphoma); and T-cell NHL, suchas precursor T-lymphoblastic lymphoma/leukemia, peripheral T-celllymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosisfungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplasticlarge cell lymphoma); lymphoma of an immune privileged site (e.g.,cerebral lymphoma, ocular lymphoma, lymphoma of the placenta, lymphomaof the fetus, testicular lymphoma); a mixture of one or moreleukemia/lymphoma as described above; myelodysplasia; and multiplemyeloma (MM).

The term “inflammatory disease” refers to a disease caused by, resultingfrom, or resulting in inflammation. The term “inflammatory disease” mayalso refer to a dysregulated inflammatory reaction that causes anexaggerated response by macrophages, granulocytes, and/or T-lymphocytesleading to abnormal tissue damage and/or cell death. An inflammatorydisease can be either an acute or chronic inflammatory condition and canresult from infections or non-infectious causes. Inflammatory diseasesinclude, without limitation, atherosclerosis, arteriosclerosis,autoimmune disorders, multiple sclerosis, systemic lupus erythematosus,polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis,tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis,rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giantcell arteritis, progressive systemic sclerosis (scleroderma), ankylosingspondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid,diabetes (e.g., Type I), myasthenia gravis, Hashimoto's thyroiditis,Graves' disease, Goodpasture's disease, mixed connective tissue disease,sclerosing cholangitis, inflammatory bowel disease, Crohn's disease,ulcerative colitis, pernicious anemia, inflammatory dermatoses, usualinterstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis,berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamativeinterstitial pneumonia, lymphoid interstitial pneumonia, giant cellinterstitial pneumonia, cellular interstitial pneumonia, extrinsicallergic alveolitis, Wegener's granulomatosis and related forms ofangiitis (temporal arteritis and polyarteritis nodosa), inflammatorydermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g.,poison ivy dermatitis), pneumonia, respiratory tract inflammation, AdultRespiratory Distress Syndrome (ARDS), encephalitis, immediatehypersensitivity reactions, asthma, hayfever, allergies, acuteanaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis,cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury),reperfusion injury, allograft rejection, host-versus-graft rejection,appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis,cervicitis, cholangitis, chorioamnionitis, conjunctivitis,dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis,myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis,osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis,salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis,urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis,vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, opticneuritis, temporal arteritis, transverse myelitis, necrotizingfasciitis, and necrotizing enterocolitis. An ocular inflammatory diseaseincludes, but is not limited to, post-surgical inflammation.

An “autoimmune disease” refers to a disease arising from aninappropriate immune response of the body of a subject againstsubstances and tissues normally present in the body. In other words, theimmune system mistakes some part of the body as a pathogen and attacksits own cells. This may be restricted to certain organs (e.g., inautoimmune thyroiditis) or involve a particular tissue in differentplaces (e.g., Goodpasture's disease which may affect the basementmembrane in both the lung and kidney). The treatment of autoimmunediseases is typically with immunosuppression, e.g., medications whichdecrease the immune response. Exemplary autoimmune diseases include, butare not limited to, glomerulonephritis, Goodpasture's syndrome,necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemiclupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemiclupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis,dermatomyositis/polymyositis, anti-phospholipid antibody syndrome,scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g.,Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjogren'ssyndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis,Lyme disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, andcardiomyopathy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of a BCA assay, and of caspase activity inparental (DU145) and high metastatic (DU145LN4) prostate cancer cellsupon treatment of compound OBD9. Cells were seeded in 6-well dishes at50% confluence. Cells were treated with the compound OBD9 after 24hours. 48 hours later, cells were lysed with lysis buffer and proteinwas collected and quantified with the BCA assay (Invitrogen). 20micrograms of protein were loaded on 10% polyacrylamide gels. The gelswere blotted onto nitrocellulose and stained with rabbit antibody toPARP-1 and Caspase-3 (both from Cell Signaling) and then visualized withgoat, anti-rabbit HRP-conjugated antibody and HRP conjugated GAPDH. FIG.1 shows that the compound OBD9 induces apoptosis in parental (DU145) andhigh metastatic (DU145LN4) prostate cancer cells.

FIG. 2 shows a tubulin polymerization assay for selected compound OBD9.Tubulin polymerization was measured using the tubulin polymerizationassay kit from Cytoskeleton Inc., which measures tubulin polymerizationkinetic via fluorescent enhancement to the incorporation of afluorescent reporter into microtubules as polymerization takes place.FIG. 2 shows that OBD9 disrupts (inhibits) tubulin polymerization.

FIG. 3 shows the effects of two OBD compounds (OBD9 and OBD17) onviability of prostate cancer cell lines (DU145, PC3, and PC3MLN4) and onviability of lung cancer lines (A549, H157, and PC9). 5000 cells wereseeded in each well of 96 well plates. 24 hours later, the wells weretreated with DMSO or the OBD compounds (OBD9 and OBD17) at therespective indicated concentrations (0.013 μM, 0.04 μM, 0.12 μM, 0.37μM, 1.1 μM, 3.3 μM, or 10 μM). 72 hours after treatment, the cells wereanalyzed using the MTT cell viability assay (Sigma).

FIG. 4 shows imaging of microtubule stability in in PC3M-prostate cancercells. Cells were seeded on glass coverslips. 24 hours later, cells weretreated with compound OBD9. After the indicated times (24 hours, 48hours, and 72 hours), cells were fixed with paraformaldehyde (4% inPBS), permeabilized Triton-X100 (0.02% in Phosphate buffered saline),then stained with mouse antibody to human tubulin (1:200 dilution) andthen with 1:400 goat anti-mouse IgC (Invitrogen) and viewed via confocalmicroscopy at (63× objective). FIG. 4 shows that OBD9 interferes withmicrotubule (tubulin) stability in PC3M-prostate cancer cells.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The present disclosure provides compounds of Formula (I). The compoundsdescribed herein are useful in treating and/or preventing proliferativediseases (e.g., cancer). The compounds may act by inhibiting growth ofcells (e.g., aggressive cancer cells). Also provided in the presentdisclosure are pharmaceutical compositions, kits, methods, and usesincluding a compound described herein.

Compounds

One aspect of the present disclosure relates to compounds of Formula (I)as described herein. The compounds described herein are compounds thatare useful in treating and/or preventing proliferative diseases in asubject. The compounds may also be useful for contacting a biologicalsample, tissue, or cell with an effective amount of a compound orpharmaceutical composition described herein. In certain embodiments, acompound described herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments, a compound described herein isa compound of Formula (I), or a pharmaceutically acceptable saltthereof.

In certain embodiments, a compound described herein is of Formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, wherein:

R¹ is independently substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl;

R² is independently substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A), —N(R^(B))₂, or—SR^(A);

R^(A) is substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl or an oxygen protecting group when attached to an oxygen atomor a nitrogen protecting group when attached to a nitrogen atom;

each occurrence of R^(B) is independently substituted or unsubstitutedalkyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl; or a nitrogen protecting group;or optionally two instances of R^(B) are joined to form a substituted orunsubstituted, heterocyclic ring, or substituted or unsubstituted,heteroaryl ring;

R³ is independently hydrogen, substituted or unsubstituted C₁₋₆ alkyl,or a nitrogen protecting group; and

R⁴ is independently hydrogen, substituted or unsubstituted C₁₋₆ alkyl,or a nitrogen protecting group.

Formula (I) includes substituent R¹. In certain embodiments, R¹ issubstituted or unsubstituted alkyl (e.g., substituted or unsubstitutedC₁₋₆ alkyl). In certain embodiments, R¹ is independently —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃. In certain embodiments, R¹ is substitutedalkyl, e.g., heterocyclalkyl. In certain embodiments, R¹ is of theformula:

In certain embodiments, R¹ is of the formula:

In certain embodiments, R¹ is substituted or unsubstituted carbocyclyl(e.g., substituted or unsubstituted, 3- to 7-membered, monocycliccarbocyclyl comprising zero, one, or two double bonds in the carbocyclicring system). In certain embodiments, R¹ is substituted or unsubstitutedheterocyclyl (e.g., substituted or unsubstituted, 3- to 9-membered,monocyclic heterocyclyl comprising zero, one, or two double bonds in theheterocyclic ring system, wherein one, two, or three atoms in theheterocyclic ring system are independently nitrogen, oxygen, or sulfur).In certain embodiments, R¹ is of the formula:

In certain embodiments, R¹ is of the formula:

In certain embodiments, R¹ is —(CH₂)_(a)N(R^(A1))₂, a is 1, 2, 3, 4, 5,or 6, and each occurrence of R^(A1) is independently hydrogen, orsubstituted or unsubstituted C₁₋₆ alkyl (e.g., R¹ is —(CH₂)₂NMe₂)). Incertain embodiments, R¹ is —(CH₂)₃NMe₂). In certain embodiments, R^(A1)is independently —CH₂CH₃, or —CH₂CH₂CH₃.

Formula (I) includes substituent R². In certain embodiments, R² issubstituted or unsubstituted acyl (e.g., acetyl). In certainembodiments, R² is of the formula:

In certain embodiments, R^(A2) is independently hydrogen, halogen (e.g.,F, Cl, Br, or I), or —N(R^(C))₂. In certain embodiments, R^(A2) is ofthe formula:

In certain embodiments, R^(A2) is of the formula:

In certain embodiments, R^(C) is independently substituted orunsubstituted alkyl, or substituted or unsubstituted heterocyclyl. WhenFormula (I) includes two or more instances of the substituent R^(C), anytwo instances of R^(C) may be the same or different from each other. Incertain embodiments, at least one instance of R^(C) is substituted orunsubstituted C₁₋₆ alkyl (e.g., -Me). In certain embodiments, at leastone instance of R^(C) is substituted or unsubstituted heterocyclyl(e.g., substituted or unsubstituted, 3- to 9-membered, monocyclicheterocyclyl comprising zero, one, or two double bonds in theheterocyclic ring system, wherein one, two, or three atoms in theheterocyclic ring system are independently nitrogen, oxygen, or sulfur).

In certain embodiments, R² is —OR^(A). In certain embodiments, R^(A) issubstituted or unsubstituted carbocyclyl (e.g., substituted orunsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero,one, or two double bonds in the carbocyclic ring system). In certainembodiments, R^(A) is substituted or unsubstituted heterocyclyl (e.g.,substituted or unsubstituted, 3- to 9-membered, monocyclic heterocyclylcomprising zero, one, or two double bonds in the heterocyclic ringsystem, wherein one, two, or three atoms in the heterocyclic ring systemare independently nitrogen, oxygen, or sulfur). In certain embodiments,R^(A) is a substituted or unsubstituted, aryl ring (e.g., substituted orunsubstituted, 6- to 10-membered aryl). In certain embodiments, R² is—OR^(A) (e.g. —O(substituted or unsubstituted phenyl) (e.g., —OPh)).

In certain embodiments, R² is of the formula:

wherein R^(A3) is —N(R^(A4)). In certain embodiments, R^(A4) isindependently substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In certain embodiments, R² is of the formula:

wherein R^(A3) is —N(R^(A4))₂. In certain embodiments, two instances ofR^(A4) are joined to form a substituted or unsubstituted, heterocyclicring (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclicheterocyclic ring comprising zero, one, or two double bonds in theheterocyclic ring system, wherein one, two, or three atoms in theheterocyclic ring system are independently nitrogen, oxygen, or sulfur).In certain embodiments, two instances of R^(A4) are joined to form asubstituted or unsubstituted heteroaryl ring (e.g., substituted orunsubstituted, 5- to 6-membered, monocyclic heteroaryl ring, whereinone, two, three, or four atoms in the heteroaryl ring system areindependently nitrogen, oxygen, or sulfur). In certain embodiments,R^(A3) is of the formula:

In certain embodiments, R² is —SR^(A). In certain embodiments, R^(A) issubstituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(A)is substituted or unsubstituted benzyl, or substituted or unsubstitutedphenyl.

Formula (I) includes substituent R³. In certain embodiments, R³ is H. Incertain embodiments, R³ is substituted or unsubstituted alkyl (e.g.,substituted or unsubstituted C₁₋₆ alkyl). In certain embodiments, R³ isa nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOCor Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc),trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

Formula (I) includes substituent R⁴. In certain embodiments, R⁴ is H. Incertain embodiments, R⁴ is substituted or unsubstituted alkyl (e.g.,substituted or unsubstituted C₁₋₆ alkyl). In certain embodiments, R⁴ isa nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOCor Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc),trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

In certain embodiments, the compound of Formula (I) is of the followingformula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof.Pharmaceutical Compositions, Kits, and Administration

The present disclosure provides pharmaceutical compositions comprising acompound described herein, or a pharmaceutically acceptable saltthereof, and optionally a pharmaceutically acceptable excipient. Incertain embodiments, a pharmaceutical composition described hereincomprises a compound described herein, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient. Thepharmaceutical compositions described herein are useful in treatingand/or preventing proliferative diseases (e.g., cancer (e.g., lungcancer, breast cancer, leukemia, lymphoma, melanoma, multiple myeloma,Ewing's sarcoma, osteosarcoma, brain cancer, neuroblastoma), benignneoplasms, angiogenesis, inflammatory diseases, autoinflammatorydiseases, and autoimmune diseases) in a subject, biological sample,tissue, or cell.

In certain embodiments, a subject being treated herein is an animal. Theanimal may be of either sex and may be at any stage of development. Incertain embodiments, the subject is a human. In certain embodiments, thesubject is a non-human animal. In certain embodiments, the subject is amammal (e.g., non-human mammal). In certain embodiments, the subject isa domesticated animal, such as a dog, cat, cow, pig, horse, sheep, orgoat. In certain embodiments, a subject being treated herein is acompanion animal such as a dog or cat. In certain embodiments, a subjectbeing treated herein is a livestock animal such as a cow, pig, horse,sheep, or goat. In certain embodiments, a subject being treated hereinis a zoo animal. In another embodiment, a subject being treated hereinis a research animal such as a rodent (e.g., mouse, rat), dog, pig, ornon-human primate. In certain embodiments, the animal is a geneticallyengineered animal. In certain embodiments, the animal is a transgenic orgenetically engineered animal (e.g., transgenic mice and transgenicpigs). In certain embodiments, a subject described herein is a fish orreptile.

In certain embodiments, the cell contacted with an effective amount of acompound or pharmaceutical composition described herein is in vitro. Incertain embodiments, the contacted cell is ex vivo. In certainembodiments, the cell described herein is in vivo. In certainembodiments, the cell described herein is a malignant cell (e.g.,malignant blood cell).

In certain embodiments, the compound described herein is provided in aneffective amount in the pharmaceutical composition. In certainembodiments, the effective amount is a therapeutically effective amount(e.g., amount effective for treating a proliferative disease in asubject in need thereof). In certain embodiments, the proliferativedisease is cancer. In certain embodiments, the proliferative disease ismetastatic cancer. In certain embodiments, the effective amount is aprophylactically effective amount (e.g., amount effective for preventinga proliferative disease in a subject in need thereof and/or for keepinga subject in need thereof in remission of a proliferative disease).

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include bringing the compound described herein (i.e., the“active ingredient”) into association with a carrier or excipient,and/or one or more other accessory ingredients, and then, if necessaryand/or desirable, shaping, and/or packaging the product into a desiredsingle- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.A “unit dose” is a discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient which would be administered to a subject and/or a convenientfraction of such a dosage, such as one-half or one-third of such adosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition described herein will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.The composition may comprise between 0.1% and 100% (w/w) activeingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugatesdescribed herein are mixed with solubilizing agents such as Cremophor®,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension, or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P., and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or di-glycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform may be accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates describedherein with suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol, or a suppository wax which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets, and pills, thedosage form may include a buffering agent.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the art of pharmacology. Theymay optionally comprise opacifying agents and can be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of encapsulating compositions which can be used includepolymeric substances and waxes. Solid compositions of a similar type canbe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like.

The active ingredient can be in a micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings, and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose, or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of encapsulating agents which can be usedinclude polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of a compounddescribed herein may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants, and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier or excipient and/or any neededpreservatives and/or buffers as can be required. Additionally, thepresent disclosure contemplates the use of transdermal patches, whichoften have the added advantage of providing controlled delivery of anactive ingredient to the body. Such dosage forms can be prepared, forexample, by dissolving and/or dispensing the active ingredient in theproper medium. Alternatively or additionally, the rate can be controlledby either providing a rate controlling membrane and/or by dispersing theactive ingredient in a polymer matrix and/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices. Intradermalcompositions can be administered by devices which limit the effectivepenetration length of a needle into the skin. Alternatively oradditionally, conventional syringes can be used in the classical mantouxmethod of intradermal administration. Jet injection devices whichdeliver liquid formulations to the dermis via a liquid jet injectorand/or via a needle which pierces the stratum corneum and produces a jetwhich reaches the dermis are suitable. Ballistic powder/particledelivery devices which use compressed gas to accelerate the compound inpowder form through the outer layers of the skin to the dermis aresuitable.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi-liquid preparations such as liniments,lotions, oil-in-water and/or water-in-oil emulsions such as creams,ointments, and/or pastes, and/or solutions and/or suspensions. Topicallyadministrable formulations may, for example, comprise from about 1% toabout 10% (w/w) active ingredient, although the concentration of theactive ingredient can be as high as the solubility limit of the activeingredient in the solvent. Formulations for topical administration mayfurther comprise one or more of the additional ingredients describedherein.

A pharmaceutical composition described herein can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Such a formulation may comprise dry particles whichcomprise the active ingredient and which have a diameter in the rangefrom about 0.5 to about 7 nanometers, or from about 1 to about 6nanometers. Such compositions are conveniently in the form of drypowders for administration using a device comprising a dry powderreservoir to which a stream of propellant can be directed to dispersethe powder and/or using a self-propelling solvent/powder dispensingcontainer such as a device comprising the active ingredient dissolvedand/or suspended in a low-boiling propellant in a sealed container. Suchpowders comprise particles wherein at least 98% of the particles byweight have a diameter greater than 0.5 nanometers and at least 95% ofthe particles by number have a diameter less than 7 nanometers.Alternatively, at least 95% of the particles by weight have a diametergreater than 1 nanometer and at least 90% of the particles by numberhave a diameter less than 6 nanometers. Dry powder compositions mayinclude a solid fine powder diluent such as sugar and am convenientlyprovided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions described herein formulated for pulmonarydelivery may provide the active ingredient in the form of droplets of asolution and/or suspension. Such formulations can be prepared, packaged,and/or sold as aqueous and/or dilute alcoholic solutions and/orsuspensions, optionally sterile, comprising the active ingredient, andmay conveniently be administered using any nebulization and/oratomization device. Such formulations may further comprise one or moreadditional ingredients including, but not limited to, a flavoring agentsuch as saccharin sodium, a volatile oil, a buffering agent, a surfaceactive agent, and/or a preservative such as methylhydroxybenzoate. Thedroplets provided by this route of administration may have an averagediameter in the range from about 0.1 to about 200 nanometers.

Formulations described herein as being useful for pulmonary delivery areuseful for intranasal delivery of a pharmaceutical composition describedherein. Another formulation suitable for intranasal administration is acoarse powder comprising the active ingredient and having an averageparticle from about 0.2 to 500 micrometers. Such a formulation isadministered by rapid inhalation through the nasal passage from acontainer of the powder held close to the nares.

Formulations for nasal administration may, for example, comprise fromabout as little as 0.1% (w/w) to as much as 100% (w/w) of the activeingredient, and may comprise one or more of the additional ingredientsdescribed herein. A pharmaceutical composition described herein can beprepared, packaged, and/or sold in a formulation for buccaladministration. Such formulations may, for example, be in the form oftablets and/or lozenges made using conventional methods, and maycontain, for example, 0.1 to 20% (w/w) active ingredient, the balancecomprising an orally dissolvable and/or degradable composition and,optionally, one or more of the additional ingredients described herein.Alternately, formulations for buccal administration may comprise apowder and/or an aerosolized and/or atomized solution and/or suspensioncomprising the active ingredient. Such powdered, aerosolized, and/oraerosolized formulations, when dispersed, may have an average particleand/or droplet size in the range from about 0.1 to about 200 nanometers,and may further comprise one or more of the additional ingredientsdescribed herein.

A pharmaceutical composition described herein can be prepared, packaged,and/or sold in a formulation for ophthalmic administration. Suchformulations may, for example, be in the form of eye drops including,for example, a 0.1-1.0% (w/w) solution and/or suspension of the activeingredient in an aqueous or oily liquid carrier or excipient. Such dropsmay further comprise buffering agents, salts, and/or one or more otherof the additional ingredients described herein. Otherophthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are alsocontemplated as being within the scope of this disclosure.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, such compositions are generallysuitable for administration to animals of all sorts. Modification ofpharmaceutical compositions suitable for administration to humans inorder to render the compositions suitable for administration to variousanimals is well understood, and the ordinarily skilled veterinarypharmacologist can design and/or perform such modification with ordinaryexperimentation.

The compounds provided herein are typically formulated in dosage unitform for ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositionsdescribed herein will be decided by a physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disease being treated and the severity of thedisorder; the activity of the specific active ingredient employed, thespecific composition employed; the age, body weight, general health,sex, and diet of the subject; the time of administration, route ofadministration, and rate of excretion of the specific active ingredientemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific active ingredient employed; and likefactors well known in the medical arts.

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, intradermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, buccal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general, the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration). In certain embodiments, the compoundor pharmaceutical composition described herein is suitable for topicaladministration to the eye of a subject.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound, mode of administration,and the like. An effective amount may be included in a single dose(e.g., single oral dose) or multiple doses (e.g., multiple oral doses).In certain embodiments, when multiple doses are administered to asubject or applied to a biological sample, tissue, or cell, any twodoses of the multiple doses include different or substantially the sameamounts of a compound described herein. In certain embodiments, whenmultiple doses are administered to a subject or applied to a biologicalsample, tissue, or cell, the frequency of administering the multipledoses to the subject or applying the multiple doses to the tissue orcell is three doses a day, two doses a day, one dose a day, one doseevery other day, one dose every third day, one dose every week, one doseevery two weeks, one dose every three weeks, or one dose every fourweeks. In certain embodiments, the frequency of administering themultiple doses to the subject or applying the multiple doses to thetissue or cell is one dose per day. In certain embodiments, thefrequency of administering the multiple doses to the subject or applyingthe multiple doses to the tissue or cell is two doses per day. Incertain embodiments, the frequency of administering the multiple dosesto the subject or applying the multiple doses to the tissue or cell isthree doses per day. In certain embodiments, when multiple doses areadministered to a subject or applied to a biological sample, tissue, orcell, the duration between the first dose and last dose of the multipledoses is one day, two days, four days, one week, two weeks, three weeks,one month, two months, three months, four months, six months, ninemonths, one year, two years, three years, four years, five years, sevenyears, ten years, fifteen years, twenty years, or the lifetime of thesubject, biological sample, tissue, or cell. In certain embodiments, theduration between the first dose and last dose of the multiple doses isthree months, six months, or one year. In certain embodiments, theduration between the first dose and last dose of the multiple doses isthe lifetime of the subject, biological sample, tissue, or cell. Incertain embodiments, a dose (e.g., a single dose, or any dose ofmultiple doses) described herein includes independently between 0.1 μgand 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg,between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg,between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g. inclusive,of a compound described herein. In certain embodiments, a dose describedherein includes independently between 1 mg and 3 mg, inclusive, of acompound described herein. In certain embodiments, a dose describedherein includes independently between 3 mg and 10 mg, inclusive, of acompound described herein. In certain embodiments, a dose describedherein includes independently between 10 mg and 30 mg, inclusive, of acompound described herein. In certain embodiments, a dose describedherein includes independently between 30 mg and 100 mg, inclusive, of acompound described herein.

Dose ranges as described herein provide guidance for the administrationof provided pharmaceutical compositions to an adult. The amount to beadministered to, for example, a child or an adolescent can be determinedby a medical practitioner or person skilled in the art and can be loweror the same as that administered to an adult.

A compound or composition, as described herein, can be administered incombination with one or more additional pharmaceutical agents (e.g.,therapeutically and/or prophylactically active agents) useful intreating and/or preventing a proliferative disease. The compounds orcompositions can be administered in combination with additionalpharmaceutical agents that improve their activity (e.g., activity (e.g.,potency and/or efficacy) in treating a proliferative disease in asubject in need thereof, and/or in preventing a proliferative disease ina subject in need thereof), improve bioavailability, improve safety,reduce drug resistance, reduce and/or modify metabolism, inhibitexcretion, and/or modify distribution in a subject, biological sample,tissue, or cell. It will also be appreciated that the therapy employedmay achieve a desired effect for the same disorder, and/or it mayachieve different effects. In certain embodiments, a pharmaceuticalcomposition described herein including a compound described herein andan additional pharmaceutical agent shows a synergistic effect that isabsent in a pharmaceutical composition including one of the compound andthe additional pharmaceutical agent, but not both.

The compound or composition can be administered concurrently with, priorto, or subsequent to one or more additional pharmaceutical agents, whichmay be useful as, e.g., combination therapies in treating and/orpreventing a proliferative disease. Pharmaceutical agents includetherapeutically active agents. Pharmaceutical agents also includeprophylactically active agents. Pharmaceutical agents include smallorganic molecules such as drug compounds (e.g., compounds approved forhuman or veterinary use by the U.S. Food and Drug Administration asprovided in the Code of Federal Regulations (CFR)), peptides, proteins,carbohydrates, monosaccharides, oligosaccharides, polysaccharides,nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides orproteins, small molecules linked to proteins, glycoproteins, steroids,nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides,antisense oligonucleotides, lipids, hormones, vitamins, and cells. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent useful in treating a proliferative disease. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent useful in preventing a proliferative disease. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent approved by a regulatory agency (e.g., the US FDA)for treating and/or preventing a proliferative disease. Each additionalpharmaceutical agent may be administered at a dose and/or on a timeschedule determined for that pharmaceutical agent. The additionalpharmaceutical agents may also be administered together with each otherand/or with the compound or composition described herein in a singledose or administered separately in different doses. The particularcombination to employ in a regimen will take into account compatibilityof the compound described herein with the additional pharmaceuticalagent(s) and/or the desired therapeutic and/or prophylactic effect to beachieved. In general, it is expected that the additional pharmaceuticalagent(s) in combination be utilized at levels that do not exceed thelevels at which they are utilized individually. In some embodiments, thelevels utilized in combination will be lower than those utilizedindividually.

In certain embodiments, the additional pharmaceutical agent is ananti-proliferative agent (e.g., anti-cancer agent). In certainembodiments, the additional pharmaceutical agent is an anti-angiogenesisagent, anti-inflammatory agent, immunosuppressant, anti-bacterial agent,anti-viral agent, cardiovascular agent, cholesterol-lowering agent,anti-diabetic agent, anti-allergic agent, pain-relieving agent, or acombination thereof. In certain embodiments, the compounds describedherein or pharmaceutical compositions can be administered in combinationwith an anti-cancer therapy including, but not limited to,transplantation (e.g., bone marrow transplantation, stem celltransplantation), surgery, radiation therapy, immunotherapy, andchemotherapy.

Also encompassed by the disclosure are kits (e.g., pharmaceuticalpacks). The kits provided may comprise a pharmaceutical composition orcompound described herein and a container (e.g., a vial, ampule, bottle,syringe, and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical excipient for dilution orsuspension of a pharmaceutical composition or compound described herein.In some embodiments, the pharmaceutical composition or compounddescribed herein provided in the first container and the secondcontainer are combined to form one unit dosage form.

In certain embodiments, a kit described herein includes a firstcontainer comprising a compound or pharmaceutical composition describedherein. In certain embodiments, a kit described herein is useful intreating a proliferative disease (e.g., metastatic cancer) in a subjectin need thereof, and/or preventing a proliferative disease in a subjectin need thereof.

In certain embodiments, a kit described herein further includesinstructions for using the compound or pharmaceutical compositionincluded in the kit. A kit described herein may also include informationas required by a regulatory agency such as the U.S. Food and DrugAdministration (FDA). In certain embodiments, the information includedin the kits is prescribing information. In certain embodiments, the kitsand instructions provide for treating a proliferative disease in asubject in need thereof, and/or preventing a proliferative disease in asubject in need thereof. A kit described herein may include one or moreadditional pharmaceutical agents described herein as a separatecomposition.

Methods of Treatment

The compounds described herein may:

-   -   exhibit cytotoxic or growth inhibitory effect on cancer cell        lines maintained in vitro or in animal studies using a        scientifically acceptable cancer cell xenograft model;    -   exhibit a therapeutic profile (e.g., optimum safety and curative        effect) that is superior to existing chemotherapeutic agents;        and/or    -   exhibit a pharmacokinetic profile (e.g., increased solubility        and increased bioavailability) that is superior to existing        chemotherapeutic agents.

The present disclosure provides methods of treating a proliferativedisease in a subject in need thereof, the methods comprisingadministering to the subject an effective amount (e.g., therapeuticallyeffective amount) of a compound, or pharmaceutical composition thereof,described herein.

Another aspect of the present disclosure relates to methods ofpreventing proliferative disease in a subject in need thereof, themethods comprising administering to the subject an effective amount(e.g., prophylactically effective amount) of a compound, orpharmaceutical composition thereof, described herein.

The compounds and pharmaceutical compositions described herein areuseful in treating and/or preventing proliferative diseases. In certainembodiments, the proliferative disease is cancer. In certainembodiments, the proliferative disease is metastatic cancer. In certainembodiments, the proliferative disease is an inflammatory disease. Incertain embodiments, the proliferative disease is an autoimmune disease.

In certain embodiments, the method described herein further includesadministering to the subject an additional pharmaceutical agent. Incertain embodiments, the method described herein further includescontacting the biological sample with an additional pharmaceuticalagent. In certain embodiments, the method described herein furtherincludes contacting the tissue with an additional pharmaceutical agent.In certain embodiments, the method described herein further includescontacting the cell with an additional pharmaceutical agent. In certainembodiments, the method described herein further includes radiotherapy,immunotherapy, and/or transplantation (e.g., bone marrowtransplantation).

Uses

In another aspect, the present disclosure provides the compoundsdescribed herein for a method of treating a proliferative disease in thedisclosure.

In still another aspect, the present disclosure provides thepharmaceutical compositions described herein for use in a method oftreating a proliferative disease in the disclosure.

In still another aspect, the present disclosure provides uses of thecompounds described herein in a method of treating a proliferativedisease in the disclosure.

In further another aspect, the present disclosure provides uses of thepharmaceutical compositions described herein in a method of treating aproliferative disease in the disclosure.

EXAMPLES

In order that the present disclosure may be more fully understood, thefollowing examples are set forth. The synthetic and biological examplesdescribed in this application are offered to illustrate the compounds,pharmaceutical compositions, and methods provided herein and are not tobe construed in any way as limiting their scope.

Example 1A. Selected Compounds and Biological Activity

Table 1 below shows the results of a viability assay: the effect ofselected exemplary compounds at concentrations of 1.0 μM and 10 μM onviability.

TABLE 1 Viability Assay: Effect of Selected Compounds on Viability %viability Compound # Structure 10 μM 1.0 μM  9 (I-1) OBD9

34.3 34.9 12 (I-2)

35.2 94.5 13 (I-3)

49.1 80.9 15 (I-4)

35.3 97.4 16 (I-5)

90.3 90.1 17 (I-6) OBD17

84.8 93.9 51 (I-7)

54 (I-8)

58 (I-9)

66  (I-10)

Preparation of the Compounds

The compounds of Formula (I) provided herein can be prepared fromreadily available starting materials using the following general methodsand procedures (e.g., Examples 1 to 9). Where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvents used, butsuch conditions can be determined by those skilled in the art by routineoptimization procedures.

Example 1. Preparation of MethylN-(5-{4-[methyl(oxetan-3-yl)amino]benzoyl}-1H-1,3-benzodiazol-2-yl)carbamate

N-[4-(3,4-dinitrobenzoyl)phenyl]-N-methylacetamide

To a solution of 3,4-dinitrobenzoic acid (750 mg, 3.54 mmol) in DCM (8mL) was added (COCl₂)₂ (2.04 g, 16.08 mmol) and a drop of DMF at 0° C.;the resulting mixture was stirred at room temperature for 1 h, and thinlayer chromatography (TLC) showed the reaction was over. The reactionmixture was concentrated to give an oil. Then,N-methyl-N-phenylacetamide (0.479 g, 3.21 mmol) and AlCl₃ (1.6 g) wasadded, and the resulting mixture was stirred at 100° C. for 4 h. Thereaction mixture was diluted with water, extracted with DCM, dried overNa₂SO₄, concentrated and purified by silica gel (PE:ethyl acetate=1:1)to give a yellow oil (240 mg, 22% yield). ¹H NMR (400 MHz, CDCl₃): δ8.33 (1H), 8.17 (1H), 8.05 (d, 1H), 7.85 (d, 2H), 7.42 (d, 2H), 3.35 (s,3H), 2.05 (s, 3H). MS (ES): 344.2 (M+H)⁺.

4-(3,4-dinitrobenzoyl)-N-methylaniline

To a solution of N-[4-(3,4-dinitrobenzoyl)phenyl]-N-methylacetamide (250mg, 0.73 mmol) in water (2 mL) was added concentrated HCl (2 mmol) at 0°C., the resulting mixture was stirred at reflux overnight TLC showed thereaction was over. The reaction mixture was adjusted pH to 8 withaqueous NaOH, extracted with DCM, dried over Na₂SO₄, concentrated andpurified by silica gel (PE:ethyl acetate=3:1) to afford the titledcompound as a yellow solid (150 mg, 68% yield). ¹H NMR (400 MHz, CDCl₃):δ 8.21 (1H), 8.05-8.0 (m, 2H), 7.70 (d, 2H), 6.61 (d, 2H), 4.5 (br s,1H), 2.95 (d, 3H). MS (ES): 302.3 (M+H)⁺.

(3,4-dinitrophenyl)[4-(methylamino)phenyl]methanol

To a solution of 4-(3,4-dinitrobenzoyl)-N-methylaniline (500 mg, 0.166mmol) in MeOH (8 mL) was added NaBH₄ (123 mg, 3.22 mmol). The resultingmixture was stirred at room temperature for 1 h. TLC showed the reactionwas over. The reaction was diluted with water, extracted with DCM, driedover Na₂SO₄, and concentrated to give the titled compound as a solid.(500 mg, 100% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.94 (1H), 7.88 (d,1H), 7.72 (d, 1H), 7.11 (d, 2H), 6.58 (d, 2H), 5.80 (br s, 1H), 3.70 (brs, 1H), 2.83 (d, 3H). MS (ES): 304.0 (M+H)⁺.

(3,4-dinitrophenyl)({4-[methyl(oxetan-3-yl)amino]phenyl})methanol

To a solution of (3,4-dinitrophenyl)[4-(methylamino)phenyl]methanol (50mg, 0.166 mmol) in MeOH (1.5 mL) was added oxetan-3-one (30 mg, 0.415mmol) and acetic acid (21 mg, 0.332 mmol). The resulting mixture wasstirred at room temperature for 1 h. Then, NaBH₃(CN) (36 mg, 0.332 mmol)was added to the mixture and stirred at room temperature overnight.LC-MS (Lot #: MC0968-024-R1) showed desired product was found. Thereaction was diluted with water, extracted with DCM, dried over Na₂SO₄,concentrated and purified by silica gel to give the titled compound as asolid. (22 mg, 38% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.91 (m, 2H), 7.73(d, 1H), 7.16 (d, 2H), 6.60 (d, 2H), 5.83 (d, 1H), 4.85 (m, 2H), 4.70(m, 3H), 2.94 (s, 3H). MS (ES): 360.1 (M+H)⁺.

N-[4-(3,4-dinitrobenzoyl)phenyl]-N-methyloxetan-3-amine

To a solution of(3,4-dinitrophenyl)({4-[methyl(oxetan-3-yl)amino]phenyl})methanol (250mg, 0.696 mmol) in DCM (5 mL) was added DMP (590 mg, 1.39 mmol). Theresulting mixture was stirred at room temperature for 1 h. The reactionwas diluted with water, extracted with DCM, dried over Na₂SO₄,concentrated and purified by silica gel (PE:ethyl acetate=1:1) to givethe titled compound as a yellow solid. (0.130 g, 52% yield). MS (ES):358.1 (M−H)⁻.

4-{4-[methyl(oxetan-3-yl)amino]benzoyl}benzene-1,2-diamine

To a solution of N-[4-(3,4-dinitrobenzoyl)phenyl]-N-methyloxetan-3-amine(100 mg, 0.280 mmol) in MeOH (1.5 mL) and THF (I mL) was added Pd/C (10mg, wet, 10%). The mixture was stirred at room temperature for 1 h. Thereaction mixture was filtered and the filtrate was concentrated to givethe titled compound as a solid (Lot: mc0968-033-1, 90 mg, 100% yield,confirmed by HNMR). ¹H NMR (400 MHz, CDCl₃): δ 7.74 (d, 2H), 7.25-7.22(m, 2H), 6.70 (d, 1H), 6.60 (d, 2H). MS (ES): 298.1 (M+H)⁺.

MethylN-(5-{4-[methyl(oxetan-3-yl)amino]benzoyl}-1H-1,3-benzodiazol-2-yl)carbamate

To a solution of4-{4-[methyl(oxetan-3-yl)amino]benzoyl}benzene-1,2-diamine (90 mg, 0.303mmol) in EtOH (2 mL) was added1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (80 mg, 0.394 mmol).The mixture was stirred at reflux overnight. TLC showed the reaction wascompleted. The reaction mixture was concentrated and purified by silicagel (DCM:MeOH=15:1) to give the titled compound as a white solid (12 mg,10% yield, confirmed by LC-MS, HNMR and HPLC). ¹H NMR (400 MHz, CDCl₃)3.09 (s, 3H), 3.88 (s, 3H), 4.81-4.92 (m, 5H), 6.64 (d, 2H), 7.44-8.11(m, 6H), 10.74 (brs, 1H). MS (ES): 281.1 (M+H)⁺.

Example 2. Preparation of (3-methyloxetan-3-yl)methylN-[5-(propylsulfanyl)-1H-1,3-benzodiazol-2-yl]carbamate

The mixture of albendazole (530 mg) and 3-hydroxyl-3-methyl-oxetane (1mL) in triethylamine (15 mL) was heated at 90° C. overnight. The solventwas removed under vacuum. The desired product was isolated by silica gelchromatography (hexanes:ethyl acetate=1:1) as a white solid. MS (ES):336.5 (M+H)⁺.

Example 3. Preparation ofOxetan-3-yl-N-(5-benzoyl-1H-1,3-benzodiazol-2-yl)carbamate

The mixture of mebendazole (295 mg), 3-hydroxyloxetane (370 mg), andtriethylamine (0.5 mL) in DMF (15 mL) was heated in a microwavesynthesizer at 60° C. for 15 minutes, then 70° C. for 5 minutes. Thesolvent was removed under vacuum. The desired product was isolated bysilica gel chromatography (dichloromethane:methanol=3:1) as a whitesolid (180 mg, 53%). MS (ES): 338.5 (M+H)⁺.

Example 4. Preparation ofOxetan-3-yl-N-[5-(phenylsulfanyl)-1H-1,3-benzodiazol-2-yl]carbamate

The mixture of fenbendazole (299 mg), 3-hydroxyloxetane (370 mg), andtriethylamine (0.5 mL) in DMF (15 mL) was heated in a microwavesynthesizer at then 70° C. for 5 minutes. The solvent was removed undervacuum. The desired product was isolated by silica gel chromatography(dichloromethane:methanol=9:1) as a white solid. MS (ES): 342.4 (M+H)⁺.

Example 5. Preparation of Oxetan-3-ylN-[5-(propylsulfanyl)-JH-1,3-benzodiazol-2-yl]carbamate

The mixture of albendazole (530 mg) and 3-hydroxyloxetane (740 mg) intriethylamine was heated at 90° C. overnight. The solvent was removedunder vacuum. The desired product was isolated by silica gelchromatography (dichloromethane:methanol=40:1) as a white solid. MS(ES): 308.6 (M+H)⁺.

Example 5. Preparation of 2-(Dimethylamino)ethylN-[5-(propylsulfanyl)-1H-1,3-benzodiazol-2-yl]carbamate

The mixture of albenzadole (265 mg, 1.0 mmol) an2-(N,N-dimethylamino)ethanol (2.0 mL) in pyridine (15 mL) was heated to90-100° C. for 3 hours. The desired product was isolated by silica gelchromatography (dichloromethane:methanol 3:1) as a yellow solid. MS(ES): 323.6 (M+H)⁺.

Example 6. Preparation of 3-(dimethylamino)propylN-[5-(propylsulfanyl)-1H-1,3-benzodiazol-2-yl]carbamate

The mixture of albenzadole (530 mg, 2.0 mmol) and3-(N,N-dimethylamino)propanol (2.0 mL) in pyridine (15 mL) was heated to90-100° C. for 3 hours. The desired product was isolated by silica gelchromatography (dichloromethane:methanol=3:1) as a yellow solid. MS(ES): 337.6 (M+H)⁺.

Example 7. Preparation of 3-(dimethylamino)propylN-[5-(4-fluorobenzoyl)-1H-1,3-benzodiazol-2-yl]carbamate

The mixture of flubendazole (626 mg, 2.0 mmol) and3-(N,N-dimethylamino)propanol (2.0 mL) in pyridine (15 mL) was heated to90-100° C. for 3 hours. The desired product was isolated by silica gelchromatography (dichloromethane:methanol=2:1) as a solid. MS (ES): 385.6(M+H)⁺.

Example 8. Preparation of methylN-{5-[3-(4-methylpiperazin-1-yl)phenoxy]-1H-1,3-benzodiazol-2-yl}carbamate

3-(4-methylpiperazin-1-yl)phenol

To a stirred solution of 3-bromophenol (0.6 g, 3.5 mmol) in anhydroustoluene (12 mL) was added N-methylpiperazine (0.5 mL, 4.2 mmol),Pd₂(dba)₃ (79 mg, 0.087 mmol), ^(t)BuONa (0.933 g, 9.7 mmol) and BINAP(0.216 g, 0.35 mmol) in this sequence. The resulting solution was heatedto reflux under the protection of argon for 1 hour. HPLC indicated thereaction is complete. After cooling to room temperature (rt), 20 mL ofethyl acetate and 20 mL of water were added to the reaction mixture, andthe black precipitate was filtered. After separation of the filtrate,the water phase was extracted with ethyl acetate (20 mL×5). The combinedorganic phase was washed with brine, dried over Na₂SO₄, and concentratedunder reduced pressure to give the crude product, which was purified bycolumn chromatography (DCM:MeOH=20:1˜15:1˜10:1) to give the titledcompound (376 mg, 56%).

5-[3-(4-methylpiperazin-1-yl)phenoxy]-2-nitroaniline

To a stirred solution of 3-(4-methylpiperazin-1-yl)phenol (360 mg, 1.87mmol) in anhydrous DMF (1.5 mL) was added 60% NaH (54 mg, 2.24 mmol)slowly, followed by 5-chloro-2-nitroaniline (323 mg, 1.87 mmol) underargon. The resulting mixture was heated to 120° C. and kept overnight.The reaction was not yet complete indicated by TLC. Additional5-chloro-2-nitroaniline (968 mg) and NaH (135 mg) were added to thereaction mixture. The reaction was complete after one hour. Aftercooling, 30 mL of cold water and 30 ml of ethyl acetate were added tothe reaction mixture. The organic layer was separated and the aqueouslayer was extracted with ethyl acetate twice (30 mL, 20 mL). Thecombined organic phase was washed with brine, dried over Na₂SO₄, andfiltered. After solvent removal, purification on a silica gel columnchromatography (DCM:MeOH=50:1˜40:1˜30:1˜20:1˜10:1) was used to affordthe titled compound (406 mg, 66%).

4-[3-(4-methylpiperazin-1-yl)phenoxy]benzene-1,2-diamine

The substrate 5-[3-(4-methylpiperazin-1-yl)phenoxy]-2-nitroaniline (297mg, 0.9 mmol) was treated with zinc dust (414 mg, 6.3 mmol) in aceticacid (19 ml) for one hour at room temperature (rt). The mixture wasfiltered through celite and the filter cake was washed with DCM. Thefiltrate was then concentrated under reduced pressure. 5N NaOH was addedto the residue to pH 13, followed by DCM. The resulting precipitate wasfiltered and dried in vacuo to give the first batch product (72 mg). Thefiltrate was separated and the aqueous layer was extracted with DCM. Thecombined organic phase was dried over Na₂SO₄, concentrated under reducedpressure to give the second batch product (79 mg). HPLC indicated thetwo batches of product have similar purity. The two batches of productwere combined (151 mg, 42%) for the next step.

MethylN-{5-[3-(4-methylpiperazin-1-yl)phenoxy]-1H-1,3-benzodiazol-2-yl}carbamate

To a stirred solution of4-[3-(4-methylpiperazin-1-yl)phenoxy]benzene-1,2-diamine (139 mg, 0.46mmol) in acetic acid (4 mL) was added1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (240 mg, 1.16 mmol)under argon. The resulting solution was heated to 85° C. and kept forone hour. HPLC indicated the reaction is complete. After cooling to roomtemperature (rt), the solvent was removed under reduced pressure. 9 mLof 2N HCl was added to the residue and the mixture was stirred at roomtemperature for one hour. The mixture was then neutralized to pH 13 withaqueous 5N NaOH solution. The resulting aqueous phase was extracted withethyl acetate three times. The combined organic phase was washed withbrine, dried over Na₂SO₄. After solvent removal, sequence purificationon a silica gel column chromatography(DCM:MeOH=50:1˜40:1˜30:1˜20:1˜10:1) was used to afford the titledcompound as a pale yellow solid. ¹H NMR (400 MHz, CD₆OD): δ 7.40 (m,1H), 7.20 (m, 1H), 7.09 (s, 1H), 6.86 (d, 1H), 6.71 (d, 1H), 6.60 (s,1H), 6.45 (d, 1H), 3.86 (s, 3H), 3.22 (m, 4H), 2.75 (m, 4H), 2.46 (s,3H). MS (ES): 382.2 (M+H)⁺.

Example 9. Preparation of methylN-(5-{[6-(4-methylpiperazin-1-yl)pyridin-2-yl]oxy}-1H-1,3-benzodiazol-2-yl)carbamate

4-[(6-chloropyridin-2-yl)oxy]-2-nitroaniline

To a stirred solution of 2,6-dichloropyridine (0.48 g, 3.24 mmol),4-amino-3-nitrophenol (0.5 g, 3.24 mmol) in anhydrous DMF (15 mL) wasadded potassium carbonate (0.67 g, 4.87 mmol) under argon. The resultingmixture was heated to 120° C. overnight. After cooling, 35 mL of waterand 35 mL of ethyl acetate were added to the reaction mixture. Afterseparation of the organic layer, the aqueous layer was extracted withethyl acetate twice (100 mL, 50 mL). The combined organic phase waswashed with brine, dried over Na₂SO₄, and concentrated under reducedpressure to give the titled compound (750 mg, 87%).

4-{[6-(4-methylpiperazin-1-yl)pyridin-2-yl]oxy}-2-nitroaniline

The substrate 4-[(6-chloropyridin-2-yl)oxy]-2-nitroaniline (0.44 g, 1.5mmol) was dissolved in 8.8 mL of N-methylpiperazine. The resultingsolution was heated to reflux under argon for three hours. After coolingto room temperature (rt), 30 mL of aqueous saturated NH₄Cl solution wasadded slowly to the mixture. The resulting mixture was then extractedwith ethyl acetate (20 mL×4). The combined organic phase was dried overNa₂SO₄, and concentrated under reduced pressure to give the titledcompound for the next step.

4-{[6-(4-methylpiperazin-1-yl)pyridin-2-yl]oxy}benzene-1,2-diamine

The substrate4-{[6-(4-methylpiperazin-1-yl)pyridin-2-yl]oxy}-2-nitroaniline (595 mg,1.8 mmol) was treated with zinc dust (827 mg, 12.6 mmol) in acetic acid(39 mL) for 10 hours at room temperature (rt) The mixture was filteredthrough celite and the filter cake was washed with ethyl acetate. Thefiltrate was then concentrated under reduced pressure. 29 mL of 5N NaOHwas added to the residue, followed by 20 ml of ethyl acetate. Theresulting precipitate was filtered and dried in vacuo to give the firstbatch product (395 mg). The filtrate was separated and the aqueous layerwas extracted with ethyl acetate (20 mL×2). The combined organic phasewas dried over Na₂SO₄, and concentrated under reduced pressure to givethe second batch product (267 mg). HPLC indicated the two batch producthave similar purity. The two batches of product was combined (654 mg)for the next step.

MethylN-(5-{[6-(4-methylpiperazin-1-yl)pyridin-2-yl]oxy}-1H-1,3-benzodiazol-2-yl)carbamate

To a stirred solution of4-{[6-(4-methylpiperazin-1-yl)pyridin-2-yl]oxy}benzene-1,2-diamine (290mg, 0.97 mmol) in acetic acid (8 mL) was added1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (499 mg, 2.42 mmol)under argon. The resulting solution was heated to 85° C. and kept for 30min. HPLC indicated the reaction is complete. After cooling to roomtemperature (rt), the solvent was removed under reduced pressure. 15 mLof 2N HCl was added to the residue and the mixture was stirred at roomtemperature (rt) for one hour. The mixture was then neutralized to pH 13with aqueous 5N NaOH solution. The resulting aqueous phase was extractedwith ethyl acetate three times. The combined organic phase was driedover Na₂SO₄, and concentrated under reduced pressure to give the crudeproduct, which was purified by sequential column chromatography(DCM:MeOH=50:1˜40:1˜30:1˜20:1˜10:1) to afford the titled compound (94mg, 25%) as a pale yellow solid. ¹H NMR (400 MHz, CD₆OD): δ 7.65 (m,2H), 7.40 (s, 1H), 7.24 (d, 1H), 6.62 (d, 1H), 6.40 (d, 1H), 4.24 (d,2H), 3.98 (s, 3H), 3.50 (m, 2H), 3.10 (m, 4H), 2.90 (s, 3H). MS (ES):383.2 (M+H)⁺.

EQUIVALENTS AND SCOPE

In the claims, articles such as “a,” “an,” and “the” may mean one ormore than one unless indicated to the contrary or otherwise evident fromthe context. Claims or descriptions that include “or” between one ormore members of a group are considered satisfied if one, more than one,or all of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior an may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A method of treating cancer in a subject in needthereof, the method comprising administering to the subject an effectiveamount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ issubstituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, or substituted or unsubstituted heterocyclyl; R² issubstituted or unsubstituted heteroaryl, —OR^(A), —N(R^(B))₂,

R^(A) is substituted or unsubstituted heterocyclyl; R^(A2) is—N(R^(C))₂, wherein each instance of R^(C) is independently substitutedor unsubstituted alkyl, or substituted or unsubstituted heterocyclyl;R^(A3) is —N(R^(A4))₂, wherein each instance of R^(A4) is independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; or twoinstances of R^(A4) are joined to form a substituted or unsubstituted,heterocyclic ring, or substituted or unsubstituted, heteroaryl ring;each occurrence of R^(B) is independently substituted or unsubstitutedalkyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl; or a nitrogen protecting group;or two instances of R^(B) are joined to form a substituted orunsubstituted, heterocyclic ring, or substituted or unsubstituted,heteroaryl ring; R³ is hydrogen, substituted or unsubstituted C₁₋₆alkyl, or a nitrogen protecting group; and R⁴ is hydrogen, substitutedor unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group.
 2. Themethod of claim 1, wherein the cancer is metastatic cancer.
 3. Themethod of claim 1, wherein the cancer is lung cancer.
 4. The method ofclaim 1, wherein the cancer is prostate cancer.
 5. The method of claim1, wherein R¹ is of the formula:


6. The method of claim 1, wherein R¹ is substituted or unsubstitutedC₁₋₆ alkyl.
 7. The method of claim 1, wherein R¹ is of the formula:

wherein: each instance of R^(A1) is independently substituted orunsubstituted C₁₋₆ alkyl; and a is 1, 2, or
 3. 8. The method of claim 1,wherein R¹ is —CH₂CH₂N(CH₃)₂ or —CH₂CH₂CH₂N(CH₃)₂.
 9. The method ofclaim 1, wherein R² is of the formula:

wherein: R^(A2) is —N(R^(C))₂; and each instance of R^(C) isindependently substituted or unsubstituted alkyl, or substituted orunsubstituted heterocyclyl.
 10. The method of claim 9, wherein R^(A2) isof the formula:


11. The method of claim 1, wherein R² is —OR^(A), and R^(A) issubstituted or unsubstituted heterocyclyl.
 12. The method of claim 1,wherein R² is of the formula:

wherein: R^(A3) is —N(R^(A4))₂, and two instances of R^(A4) are joinedto form a substituted or unsubstituted, heterocyclic ring, orsubstituted or unsubstituted, heteroaryl ring.
 13. The method of claim1, wherein R² is of the formula:

wherein: R^(A3) is —N(R^(A4))₂, and two instances of R^(A4) are joinedto form a substituted or unsubstituted, heterocyclic ring, orsubstituted or unsubstituted, heteroaryl ring.
 14. The method of claim1, wherein R³ is hydrogen.
 15. The method of claim 1, wherein R⁴ ishydrogen.
 16. The method of claim 1, wherein the compound is of theformula:

or a pharmaceutically acceptable salt thereof.
 17. A method of treatingcancer in a subject in need thereof, the method comprising administeringto the subject an effective amount of a compound of formula:

or a pharmaceutically acceptable salt thereof.
 18. The method of claim17, wherein the cancer is metastatic cancer.
 19. The method of claim 17,wherein the cancer is lung cancer.
 20. The method of claim 17, whereinthe cancer is prostate cancer.